From bench to bedside: combining electrophysiological experiments and mathematical modeling to develop a novel anti-arrhythmic therapy
The TASK-1 potassium channel is strongly upregulated in the atria of patients with atrial fibrillation (AF). Cellular electrophysiological investigations in human atrial cardiomyocytes combined with mathematical models of atrial cardiomyocytes showed that the TASK-1 channel is an important regulator of the atrial action potential duration and contributes to the pathophysiology of AF and systolic heart failure. In a large animal model of AF, in presence or absence of combined heart failure, the effect of a therapeutic TASK-1 modulation was tested and characterized by electrophysiological mapping. Using in-silico modeling of the TASK-1 ion channel pore and compound docking simulations, a new specific TASK-1 inhibitor was identified. The new inhibitor could successfully inhibit AF in the pig model. After quantitatively characterizing the effect of TASK-1 inhibition by a combination of electrophysiological experiments and computational modeling, the new TASK-1 inhibitor was translated to clinical application within the DOCTOS (doxapram conversion to sinus rhythm) trial. To translate our mechanistic findings to the clinic, our integrative approach combines molecular biology and cellular electrophysiology experiments, data from clinical records and animal studies, molecular dynamics simulations and mechanistic modeling. In this context, computational modeling was essential for bridging between ion channel functions in single cells and cardiac pathophysiology.